5DKJ

Yeast 20S proteasome in complex with octreotide-PI


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 

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Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Targeted Delivery of Proteasome Inhibitors to Somatostatin-Receptor-Expressing Cancer Cells by Octreotide Conjugation.

Beck, P.Cui, H.Hegemann, J.D.Marahiel, M.A.Kruger, A.Groll, M.

(2015) ChemMedChem 10: 1969-1973

  • DOI: https://doi.org/10.1002/cmdc.201500449
  • Primary Citation of Related Structures:  
    5DKI, 5DKJ

  • PubMed Abstract: 

    Clinical application of proteasome inhibitors (PIs) is so far limited to peripheral blood cancers due to the pronounced cytotoxicity towards all cell types. Targeted delivery of PIs could permit the treatment of other cancers along with decreasing side effects. Herein we describe the first small-molecule proteasome inhibitor conjugate for targeted delivery, created by fusing PIs to a synthetic ligand of somatostatin receptors, which are highly expressed in a variety of tumors. X-ray crystallographic studies and in vitro IC50 measurements demonstrated that addition of the cyclopeptide octreotide as a targeting vehicle does not affect the PI's binding mode. The cytotoxicity of the conjugate against somatostatin-receptor-expressing cells was up to 11-fold higher than that of a non-targeting surrogate. We have therefore established PIs as a new payload for drug conjugates and have shown that targeted delivery thereof could be a promising approach for the broader application of this FDA-approved class of compounds.


  • Organizational Affiliation

    Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany. pbeck@tum.de.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-2
A, O
250Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-3
B, P
258Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-4
C, Q
254Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-5
D, R
260Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-6
E, S
234Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
Probable proteasome subunit alpha type-7
F, T
288Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-1
G, U
252Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-2
H, V
232Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-3
I, W
205Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-4
J, X
198Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 11
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-5
K, Y
212Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-6
L, Z
222Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 13
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-7AA [auth a],
M
246Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 14
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-1BA [auth b],
N
196Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5BY
Query on 5BY

Download Ideal Coordinates CCD File 
EA [auth H]
IA [auth K]
LA [auth N]
PA [auth V]
QA [auth Y]
EA [auth H],
IA [auth K],
LA [auth N],
PA [auth V],
QA [auth Y],
SA [auth b]
{2-[2-(2-{4-[(1E)-4-{[(2S)-1-{[(1R)-1-(dihydroxyboranyl)-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]amino}-4-oxobut-1-en-1-yl]-1H-1,2,3-triazol-1-yl}ethoxy)ethoxy]ethoxy}acetic acid
C28 H42 B N5 O9
GVUUMFJCOIHUSH-QCRXNWCPSA-N
CL
Query on CL

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DA [auth G],
NA [auth N],
OA [auth U],
TA [auth b]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

Download Ideal Coordinates CCD File 
CA [auth G]
FA [auth I]
GA [auth I]
HA [auth J]
JA [auth K]
CA [auth G],
FA [auth I],
GA [auth I],
HA [auth J],
JA [auth K],
KA [auth L],
MA [auth N],
RA [auth Z]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 136.67α = 90
b = 299.71β = 113.16
c = 145.43γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
REFMACphasing
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Research FoundationGermanyGR1861/10-1

Revision History  (Full details and data files)

  • Version 1.0: 2015-10-28
    Type: Initial release
  • Version 1.1: 2016-01-27
    Changes: Database references
  • Version 2.0: 2024-01-10
    Changes: Advisory, Atomic model, Author supporting evidence, Data collection, Database references, Derived calculations, Refinement description